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Carence précoce en donneurs de méthyles dans le cervelet : mécanismes moléculaires et épigénétiques

Abstract : Early methyl-donor deficiencies (e.g. B9 and B12 vitamins) can lead to congenital disabilities. They are behind developmental abnormalities of the brain, and are associated with the development of neurological and neurodegenerative diseases at adulthood as well. In the lab, we developed a methyl donor deficiency rat model called MDD. It has allowed us to show structure alterations of several brain areas and also locomotor coordination impairments in pups born from dams fed a MDD diet. Cerebellum is the brain structure involved in the control of this behavior and we know its development is delayed in MDD. However, the molecular mechanisms underlying methyl donor deficiency still remain misunderstood in this brain structure. In order to study genes and signaling pathways dysregulated in MDD, we performed transcriptomic analysis of deficient pups’ cerebellum. We also led miRnome analyses and histone modifications investigations with the purpose of understanding epigenomic modifications caused by MDD. We showed alterations of wnt signaling pathways in female’s cerebellum which we did not find in males. We also found that several genes involved in cerebellum’s development and synaptic function were dysregulated in females. Regarding epigenomic regulation, acetylation and methylation of histone marks were also modified in females. Finally, we chose miR-344-5p as an interesting candidate to study more specific epigenetic modifications. Its expression is decreased in MDD and it seems to be involved in cellular death control, according to our first results. These results shed light on global dysregulations, in a sex-dependent manner, as a consequence of methyl donor deficiency but also more specific alterations. A better understanding of the molecular mechanisms taking place in response to MDD could help us to link methyl donor deficiency, brain development and neurodegenerative pathologies occurrence at adulthood
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https://tel.archives-ouvertes.fr/tel-01823903
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Submitted on : Tuesday, June 26, 2018 - 3:40:06 PM
Last modification on : Tuesday, October 13, 2020 - 10:47:05 AM
Long-term archiving on: : Wednesday, September 26, 2018 - 10:26:21 PM

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  • HAL Id : tel-01823903, version 1

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Jérèmy Willekens. Carence précoce en donneurs de méthyles dans le cervelet : mécanismes moléculaires et épigénétiques. Biochimie, Biologie Moléculaire. Université de Lorraine, 2017. Français. ⟨NNT : 2017LORR0303⟩. ⟨tel-01823903⟩

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